Obstructive sleep apnea is characterized by recurrent episodes of upper airway obstruction, leading to reductions in ventilation and disruption of sleep. As the severity of upper airway obstruction increases, ventilation decreases progressively, resulting in a spectrum of clinical disorders characterized by snoring and periodic obstructive hypopneas and apneas. Although obesity, and in particular central obesity, and male gender predispose to obstructive sleep apnea, the physiologic basis for these associations remains largely unknown. The current proposal will define the relationship between these risk factors and discrete intermediate physiologic traits during sleep that predispose to upper airway obstruction and hypoventilation. Our proposal is predicated on the concept that specific physiologic characteristics of upper airway function (critical pressure) and ventilatory control (maximum inspiratory airflow and inspiratory duty cycle) determine the level of ventilation during sleep. Preliminary Data indicate that obesity predisposes to alterations in critical pressure, whereas male gender is associated with disturbances in the neural control of ventilation. Our major hypothesis is that obesity and male gender predispose to specific mechanical alterations and neural responses that determine susceptibility to obstructive sleep apnea. To test this hypothesis, methods have been developed to rapidly assess baseline upper airway and ventilatory characteristics, and compensatory neural responses to upper airway obstruction during sleep. A major strength of our approach is that these physiologic phenotypes will be assessed in normal individuals who are free of confounding from sleep apnea and co-morbid conditions. In Specific Aim 1, we will determine the effect of obesity on intermediate physiologic traits that confer susceptibility to sleep apnea in normal subjects, and examine the effect of fat distribution on these phenotypes. In Specific Aim 2, we will elucidate the effect of gender on these physiologic traits, and the modulation of these characteristics by body fat distribution. Our experimental findings will lay the groundwork for further studies elucidating underlying physiologic mechanisms and phenotypic correlates of disease susceptibility in obstructive sleep apnea.